16-halo-9beta,10alpha-steroids of the pregnane series



3,437,675 16-HAL0-9/3,100c-STEROIDS OF THE PREGNANE SERIES EnghertHarmen Reel-ink, Pieter Westerhof, and Hendrik Frederik Louis Scholer,Van Houtenlaan, Weesp, Netherlands, assignors to North American PhilipsCompany, Inc., New York, N.Y., a corporation of Delaware No Drawing.Continuation of application Ser. No.

472,703, July 16, 1965. This application Aug. 30,

1967, Ser. No. 664,568

Int. Cl. C07c 169/30, 169/34 U.S. Cl. 260397.3 5 Claims ABSTRAT OF THEDISCLOSURE Novel l6-halo-9fi,10ot pregnanes are disclosed, for eX- ample16a-fluoro19/3,10a-pregn-4-ene-3,20-dione and 160cbromo-9B,l0apregna-1,4,6-triene-3,20-dione. The compounds are progestationallyactive. As a starting material 16tz-acetoxy 95,10otpregna-4,6-diene-3,20-dione is disclosed.

This application is a continuation of our copending application Ser. No.472,703 filed July 16, 1965, now abancloned.

This invention relates to novel l6-halogen-9fi,lOu-pregnanes of thegeneral Formula I wherein R represents a 3-keto-A 3-keto-A 3-keto- A3-keto-A 3-alkoXy-A or a 3-acyloXy-A -system, and hal represents achloro, bromo or fluoro atom, and a process for the manufacture thereof.

Examples of 16-halogen-9fi,IOwpregnaneS of the general Formula I are:

The 16-halogen-95,lOa-pregnanes of the general Formula I can be preparedin accordance with methods known per se for the preparation of thecorresponding steroids of the normal series.

3,437,675 Patented Apr. 8, 1969 A preferred manufacturing processconsists in reacting a compound of the general Formulas II or III:

CH3 CH3 II III .03 mo H r H 0- 0 11a IIIa wherein in the Formula IIa ORrepresents a free or esterified hydroxy group.

The reaction of the compounds of the general Formulas II and III withhydrogen fluoride, hydrogen chloride or hydrogen bromide is preferablyeffected at room temperature, e.g. at 20-25 in a non-ketonic,non-alcoholic, inert organic solvent, e.g. in an aliphatic or aromatichydrocarbon such as petroleum ether or benzene, toluene or Xylene, or ina halogenated or nitrated hydrocarbon such as methylene chloride,chloroform, carbon tetrachloride, chlorobenzene or notrobenzene,respectively, or in ethers such as diethyl ether, dioxane ortetrahydrofuran.

The hydrogen fluoride, hydrogen chloride or hydrogen bromide is suitablypassed through a solution of the compounds of the general Formulas II orIII in one of the solvents mentioned as a dry gas, e .g., for 0x5 to 10hours. The course of the reaction can be followed by thin layerchromatography or U.V. spectrometry of the reaction mixture.

The 16 halogen compounds obtained can be dehydrogenated in 1- and/ or6-position or converted into a 3-enol ether or 3-enol ester in furtherprocess steps, if desired.

The introduction of double bonds in land/or 6- position can be effectedin accordance with methods known per se from the normal series ofsteroids, e.g. by treatment with dehydrogenating agents such aschloranil or 2,3-dichloro-5,6-dicyanobenzoquinone. A A -double bond canalso be introduced with iodine pentoxide, periodic acid, seleniumdioxide, lead tetraacetate or by microbiological methods.

Methods which are known per se from the chemistry of the normal steroidscan find use for the enol etherification or enol esterification of the3-keto-A -system.

The enol esterification can, for example, be carried out by reacting thesteroid with an acylating agent in the presence of a catalyst, e.g. withisopropenyl acetate in the presence of p-toluene sulfonic acid.

The enol etherification can, for example, be carried out by reacting thesteroid with an alcohol, such as methanol, ethanol, benzyl alcohol inthe presence of a catalyst, such as p-toluene sulfonic acid, or byreacting with an orthoformic acid ester in the presence of a catalyst,e.g. with orthoformic ester ethyl ester and hydrogen chloride, or with adialkoxy propane, e.g. dimethoxy propane in methanol-dimethyl formamidein the presence of a catalyst, such as p-toluene sulfonic acid.

The alkyl group in a 3-alkoxy group is preferably an aliphatic,cycloaliphatic or araliphatic alkyl group having 1-10 C-atoms. Examplesof such groups are: methyl, ethyl, propyl, tert.-butyl, cyclopentyl,cylohexyl, benzyl and dihydropyranyl.

An esterified 17-hydroxy group is-preferably an acyloxy group of whichthe acyl residue is derived from a saturated or unsaturated aliphatic orcyloaliphatic, an araliphatic or aromatic carboxylic acid having 1-20C-atoms. Examples of such acids are: formic acid, acetic acid, pivalicacid, propionic acid, butyric acid, caproic acid, heptanoic acid, oleicacid, palmitic acid, stearic acid, succinic acid and benzoic acid.

The starting compounds of the Formulas II and III, insofar, as they arenot known, can be prepared in accordance with known methods.

Starting compounds of the Formula II, wherein OR represents a hydroxygroup can be prepared microbiologically from the correspondingunsubstituted compounds, e.g. by incubation with Sepedoniumampullosporum. The l6-hydroxy compounds can then be converted into thestarting compounds of the Formula II wherein OR represents an esterifiedhydroxy group by treatment with an acylating agent, e.g. an acidanhydride in the presence of an acid binding agent. Starting compoundsof the Formula 111 can be prepared from the corresponding l6-hydroxycompounds of the Formula II by dehydration, e.g. with catalytic amountsof p-toluene sulfonic acid in boiling benzene.

The compounds of this invention possess hormonal, in particularprogestational activity. They can be used as medicaments in the form ofpharmaceutical preparations which contain them in admixture with apharmaceutical organic or inorganic inert carrier material suitable forenteral or parenteral administration, such as, for example, water,gelatin, lactose, starch, magnesium stearate, talc, vegetable oils,gums, polyalkylene glycols or petroleum jelly. The pharmaceuticalpreparations may be in solid form (e.g. as tablets, drages,suppositories or capsules) or in a liquid form (e.g. as solutions,suspensions or emulsions). If desired, they may be sterilized and/orcontain auxiliary substances such as preserving,

stabilizing, wetting or emulsifying agents, salts for varying theosmotic pressure or buffers. They may also contain, in combination,other therapeutically valuable substances.

In the following examples all temperatures are given in degreescentigrade.

EXAMPLE 1 A stream of dry hydrogen chloride was passed through asolution of 0.5 g. of 9B,1-0a-pregna-4,16-diene-3,20-dione in 35 ml. ofchloroform for 2 hours at and for 4 hours at -25 Thereafter, thereaction mixture was allowed to stand for 18 hours at room temperatureand then taken up in ethyl acetate. The extract was washed with water,hydrogen carbonate solution and water, dried over sodium sulfate andevaporated. The residue atforded (after recrystallisation from ethylacetate/isopropyl ether) 392 mg. ofl6a-chloro-9B,10e-pregn-4-ene-3,20-dione. Melting point l52153, UV: k239 mu, e=16,800, [a] =74 (in dioxane).

The starting 9p,l0a-pregna-4,l6-diene-3,20 dione was prepared asfollows: 6.0 g. of 16a-hydroxy-9g3, lOat-pregn- 4ene-3,20-dione weredissolved in 300 ml. of benzene while heating. After the addition of 0.6g. of p-toluene sulfonic acid the solution was refluxed under nitrogen.

After 20 minutes, ca. 200 ml. of benzene were slowly distilled oif usinga short Vigreux column. The residue was taken up in ethyl acetate, theethyl acetate solution was washed with sodium hydrogen carbonatesolution, dried over sodium sulfate and evaporated. The residue wastreated with charcoal in methanolic solution and recrystallized frommethanol/isopropyl ether. There was obtained 9fi,l0a,pregna-4,1-6-diene-3,20 dione. Yield 86%, melting point 164-166", UV:)t 240 mu, e=25,300.

EXAMPLE 2 A stream of dry hydrogen chloride was passed through asolution of 500 mg. of 16a-acetoxy-9 B,10a-pregna-4,6- diene-3,20 lionein 50 ml. of chloroform for 6 hours at '0". After the addition of ethylacetate, the reaction mixture was worked up according to the procedureof Example I. There were obtained 340 mg. of 16a-chloro-9t3,10u-pregna-4,6-diene-3,20-dione. Melting point 156 (from methylenechloride/isopropyl ether). UV: A 284 mu, e=26,000, [a] =-471 (indioxane).

The same compound was prepared in an analogous manner using95,l0a-pregna-4,6,16-triene-3,20-dione andl6a-hydroxy-9B,l0ot-pregna-4,6-diene-3,ZO-dione as the startingmaterial.

The 9,8,10u-pregna-4,6,l6-triene-3,20-dione can be prepared by aprocedure analogous to that described in Example 1 by dehydration of16a-hydroxy-9/3,loot-pregna- 4,6-diene-3,20-dione. Melting point129-130", UV: k 238 and 285 mu, e=ll,700 and 25,800, respectively, [a]=-4l7 (in dioxane).

The 16oz acetoxy 9p,10ot-pregna-4,6-diene-3,20-dione used as thestarting material in the above example can be prepared by acety-lating16a-hydroxy-95,l0a-pregna-4,6 diene-3,20-dione with acetic anhydride inthe presence of pyridine. Melting point 126427 (from acetone-hexane),UV: x,,,,,,, 284 mu, $26,000, [a]- =-501 (in dioxane).

EXAMPLE 3 1.3 g. of 2,3-dichloro-5,6-dicyanobenzoquinone were added to asolution of 1.0 g. of l6a-chloro-9 3,lOu-pregna- 4,6-diene-3,20-dione in50 ml. of dioxane containing 1% of hydrogen chloride. The reactionmixture was stirred under nitrogen at room temperature for 2.5 hours.After the addition of 0.5 .g. of solid sodium hydrogen carbonatestir-ring was continued for a further 15 minutes. The solution was thenfiltered and the filtrate concentrated. By chromatography on g. ofsilicagel using benzene/acetone (9:1) as the elution agent there wasobtained 0.5 g. of l6a-chloro-9fl,10u-pregna1,4,6-triene,3,20-dione.Melting point 154 (from methylene chloride/isopropyl ether). UV: Mm,221, 251 and 300 [Tl .L, $12,600, 9,900 and 13,- 100, respectively. [a]g=--340 (in dioxane).

We claim:

1. 16-halogen-9B,loa-pregnanes of the general formula CH1 i (:0 H36 i q5 --hal wherein R is a member selected from the group consisting of a3-keto-A 3keto-A 3-k8tOA 3-keto-A 3-alkoxy-A and a B-acyIoXy-A -system,and hal is a member selected from the group consisting of chloro, bromoand fluoro.

2. A 16-halogen-9fl,IOu-pregnane of claim 1 said compound specificallybeing 16a-chloro-9fl,l0a-pregn-4-ene-3 References Cited 20 dioneLederle, J. Med. and Pharm. Chem. (1962), 5, p.950. 3. A16-halogen-9fi,loa-pregnane of claim 1 said comg g g st 2 5 and Pharm'Chem" September pound specifically being16a-ch10ro-9B,10a-pregna-4,6-diene-3,20-dione. O

4. A 16-hal0gen-95,IOa-pregnane of claim 1 said com- ROBERTS Prlma'yExammer pound specifically being 16a-ch1or0-9fl,10a-pregna-1,4,6-triene-3,20-dione.

5. 16a-acetoxy-9 3,10u-pregna-4,6-diene-3,20-di0ne.

US. Cl. X.R.

272 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,437,675 Dated April 8, 1969 Inv nt fls) ENC-BERT HARMEN REERlNK ET ALIt is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1, line 19, (in the abstract) "fluoro 1'' should read fluoro-Column 2, line 46, "notrobenzene" should read nitrobenzene Column 4,line 30, "m should read nm Column 4, line 37, "mp" should read nm sameline, [a] ShOuld rad 15 Column 4, line 52, "mp" should read nm Signedand sealed this 3rd day of M h 1970 Anew EdwardMFletcherJr, I I

o 1 Bl m Attestmg Officer Gomissioner or Pat-ants

